Macrophages are essential for both, to clear pathogens and preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR (survival associated immune-regulatory RNA), a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in a nuclear factor kappa B (NF-κB) dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis, and invasion factors, which include SIGLEC1 and MMP7. During infection with Salmonella Typhimurium, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the antiapoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator in linking macrophage survival to host-pathogen interaction and disease pathophysiology.
A. Westermann, Alexandra Schock, Diyaa Al Din Ashour et al.· Proceedings of the National...· 0 citations
Abstract Neisseria meningitidis is a human-adapted commensal pathogen that must continuously balance nutrient acquisition with stress tolerance. Here, we identify a type II-C CRISPR/Cas-associated small RNA (scaRNA) as a posttranscriptional regulator of the efeUOB operon and oxidative stress responses. Using in vitro RNA binding and structure probing assays, we show that the scaRNA interacts with the 5′ untranslated region of efeO mRNA, leading to reduced translation of this component of the ferrous iron transporter EfeUOB. Consistent with this, efeO translational fusions demonstrate repression by the scaRNA, whereas a ΔscaRNA mutant shows increased reporter expression. We further show that meningococcal Cas9 (Nme1Cas9) is able to cleave scaRNA in vitro, but in vivo phenotypes are primarily scaRNA-dependent, indicating that Nme1Cas9 contributes, at most, indirectly to this regulation. In line with this observation, comparative proteomics revealed overlapping but distinct roles of scaRNA and Nme1Cas9 in oxidative stress adaptation, energy metabolism, and ion transport. While steady-state protein abundances did not capture all scaRNA-dependent effects, functional assays confirmed that scaRNA inactivation reduces survival under oxidative stress. Together, our results identify scaRNA-mediated repression of efeO as a novel posttranscriptional mechanism that contributes to stress adaptation in meningococci. These findings expand the functional repertoire of CRISPR-associated elements and suggest a role for small RNA-based regulation in iron-related stress adaptation in a major human pathogen.
Denise Pytlik, Milan Gerovac, Thorsten Bischler et al.· microLife· 0 citations
Findings indicate that the specific identity of the CPP used plays a key role in determining its robustness against the evolution of resistance, and that laboratory evolution can illuminate the remaining gaps in the authors' knowledge on the mechanisms of action of asobiotics.
Adam J. Mulkern, T. Vu, Linda Popella et al.· bioRxiv· 3 citations
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